Depletion of cartilage collagen fibrils in mice carrying a dominant negative Col2a1 transgene affects chondrocyte differentiation |
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Authors: | Barbieri Ottavia Astigiano Simonetta Morini Monica Tavella Sara Schito Anna Corsi Alessandro Di Martino Davide Bianco Paolo Cancedda Ranieri Garofalo Silvio |
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Affiliation: | Università di Genova, Centro Biotecnologie Avanzate (Rm. C305 Largo Rosanna Benzi n.10, 16132 Genova, Italy. |
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Abstract: | We have generated transgenic mice harboring the deletion of exon 48 in the mouse 1(II) procollagen gene (Col2a1). This was the first dominant negative mutation identified in the human 1(II) procollagen gene (COL2A1). Patients carrying a single allele with this mutation suffer from a severe skeletal disorder called spondyloepiphyseal dysplasia congenita (SED). Transgenic mice phenotype was neonatally lethal with severe respiratory failure, short bones, and cleft palate. Transgene mRNA was expressed at high levels. Growth plate cartilage of transgenic mice presented morphological abnormalities and reduced number of collagen type II fibrils. Chondrocytes carrying the mutation showed altered expression of several differentiation markers, like fibroblast growth factor receptor 3 (Fgfr3), Indian hedgehog (Ihh), runx2, cyclin-dependent kinase inhibitor P21CIP/WAF (Cdkn1a), and collagen type X (Col10a1), suggesting that a defective extracellular matrix (ECM) depleted of collagen fibrils affects chondrocytes differentiation and that this defect participates in the reduced endochondral bone growth observed in chondrodysplasias caused by mutations in COL2A1. skeletal dyplasias; growth plate; cartilage extracellular matrix; spondyloepiphyseal dysplasia congenita |
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